This invention relates to a novel process for the synthesis of aspalathin (3-(3,4-dihydroxyphenyl)-1-(3-beta-D-glucopyranosyl-2,4,6-trihydroxyphenyl)-1-propanone (Formula A) and analogues thereof.
Aspalathin and its analogues occur in nature in plants. Significant biological activities have been attributed to this class of compounds.
Aspalathin and its analogues consist of three building blocks:
a sugar (saccharide) moiety, typically D-glucose;
a mono- or polyhydroxylated aromatic ring, typically phloroglucinol (ring B in formula A); and
a 3-phenyl propanoid moiety, typically 3-(3′,4′-hydroxyphenyl)-1-propanone (ring A in formula A).
The sugar moiety is linked at its anomeric (C-1) position (C-1″ in formula A) to the polyhydroxylated aromatic ring via a carbon-carbon bond. Aspalathin and analogues are thus C-glycosides. The anomeric carbon in aspalathin is in the β-configuration but in analogues it can be in the β- or α-configuration. In analogues of aspalathin the sugar moiety can be any sugar, including monosaccharides, disaccharides and polysaccharides (examples include the D- and L-forms of ribose, arabinose, galactose, fructose, sucrose etc.). A sugar is defined as a polyhydroxylated aldehyde or ketone. Sugars typically have five or six carbon atoms and typically, but not always, occur as a cyclic acetal in aspalathin and analogues. The sugar moiety is normally in the free hydroxy form but may be fully or selectively derivatised. For example, it may occur as methyl or benzyl ethers or as acetates. The sugar moiety is typically an underivatised D-glucose acetal in the β-configuration, as in formula A.
The propanoid moiety is linked to the polyhydroxylated aromatic ring via a carbon-carbon bond between the aromatic ring and the carbonyl carbon on the propanoid moiety. The moiety without the sugar molecule is thus a dihydrochalcone. The propanoid moiety has a carbonyl group and can also have a double bond conjugated with the carbonyl group. In this case, the moiety of aspalathin and analogues without the sugar is a chalcone. The propanoid moiety typically has a carbonyl in the 1-position and occurs without a double bond, and is thus part of a dihydrochalcone moiety, as in formula A.
The phenyl group (ring A in formula A) on the 3-position of the propanoid moiety can have zero, one, two, three, four or five hydroxy groups on any of the available aromatic carbons. For example, the analogue with only one hydroxy can have this hydroxyl group in the 2, 3 or 4 position and the analogue with two hydroxyl groups has these typically in the 3,4-position as in formula A, but can also have these in the 2,3-position, 2,5-position, 3,5-position or 2,4-position. The analogue with three hydroxyl groups has these typically in the 3,4,5-position. The phenyl group of the propanoid moiety with one or more hydroxy groups is normally in the free hydroxy form but may be fully or selectively derivatised. For example, it may occur as methyl or benzyl ethers or as acetates.
The mono or polyhydroxylated aromatic ring (in the 1-position of the propanoid moiety) (ring B in formula A) acts as a linkage between the sugar moiety and the propanoid moiety. It can have one (in which case it is phenol), two (in which case it can be resorcinol), three (in which case it can be phloroglucinol or pyragallol) or four hydroxy groups. These hydroxy groups may be fully or selectively derivatised: for example, they may be methyl or benzyl ethers or acetates. They are typically an underivatised free phenolic phloroglucinol moiety, as in formula A.

Aspalathin is usually extracted from Aspalathus linearis (rooibos plant) and there are no known references which describes the synthesis of this compound in yields of more than 2% or less than eight steps (Yepremyan, Organic Letters, 2010, 1580-1583).
There is therefore a need for a method of synthesising aspalathin and its analogues in commercially viable quantities in a few steps from easily available starting materials.